Method for treatment of gastrointestinal secretory and ulcerogenic disease conditions or symptoms in mammals

ABSTRACT

A new class of chemical compounds and their process of preparation is described. These compounds have valuable properties as anti-secretory, anti-spasmodic, anti-ulcerogenic and anti-diarrheal agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 811,092 filed June 17, 1977,now U.S. Pat. No. 4,115,647 issued Sept. 19, 1978 which in turn is adivision of application Ser. No. 671,763 filed Mar. 30, 1976, now U.S.Pat. No. 4,058,557 issued Nov. 15, 1977.

SUMMARY OF THE INVENTION

This invention describes a new class of chemical compounds and theprocess for their preparation. This invention further describes valuablepharmaceutical preparations which are effective for producinganti-secretory, anti-spasmodic, anti-ulcerogenic and anti-diarrhealactions. This invention further describes a class of chemical compoundscalled N-oxygenated amidinoureas and the same possess an effectivedegree of activity which is capable of producing anti-secretory,anti-spasmodic, anti-ulcerogenic and anti-diarrheal properties inmammals.

BACKGROUND OF THE INVENTION

The pharmaceutical compositions which have been used as anti-ulcerogenicagents have been such as atropine, homatropine, propantheline bromide,dicyclomine hydrochloride and other compounds which are structurallydissimilar to the amidinoureas of this invention. Due to theanticholinergic properties of these compounds they are known to produceundesirable side effects such as mydriasis, xerostomia, cycloplegia andother unwanted effects.

Diarrhea is widespread among the world's population. In certaindiseases, this enteric disorder can be the cause of a high degree ofmorbidity and even mortality.

The narcotic analgesics remain the drugs of choice for treatment ofdiarrhea and dysentery. This group of drugs, however, has seriousdisadvantages. They possess the narcotic properties of producing sleepas well as analgesia. They also have physical and psychologicaldependence liabilities. Morphine and codeine remain two outstandingexamples of this group.

In 1957 a merperidine derivative, diphenoxylate, was introduced intotherapeutic regimen of diarrhea control. This agent possessesmorphine-like as well as anticholinergic properties, both of which maybe responsible for its anti-diarrheal actions. Diphenoxylate, because ofits narcotic properties, is capable of supporting morphine physicaldependence in the monkey. Overdoses in children can lead to symptoms andfatalities that are characteristic of the narcotics, e.g. respiratorydepression and reversal of morbidity with nalorphine.

We have found novel amidinoureas which are valuable pharmacologic agentspossessing useful anti-secretory, anti-spasmodic, anti-ulcerogenic andanti-diarrheal properties.

We have also found that the compounds of this invention aresubstantially free of the anticholinergic side-effects which accompanythis type of agent.

We have further found a simple and effective method for treatingduodenal and peptic ulcers.

We have also found compounds which inhibit pepsin generation.

We have also found that the compounds of this invention have aneffective degree of muscle relaxant properties which are capable ofreducing uterine spasm.

We have further found compounds of this invention to be useful incontrolling premenstrual cramps and dysmenorrhea.

We have also found that administration of the amidinoureas of thisinvention provide a simple and effective method for the treatment ofgastrointestinal, spasmolytic, ulcerogenic and diarrheal disorders.

We have found that the admidinoureas of this invention are convenientlyprepared.

We have found that the presence of the N-oxygenated group on theamidinourea moiety reduces the basicity of the molecule by a factor ofabout 1000 and is thereby valuable in that it reduces any cardiovascularside effects which would be present in compounds not having thisfeature.

DESCRIPTION AND PREFERRED EMBODIMENTS

This invention describes a novel class of chemical compounds of theformula: ##STR1## where: R₂, R₃, R₄, R₅ and R₆ may be the same ordifferent and are:

hydrogen,

halo,

loweralkyl,

haloloweralkyl,

nitro,

amino,

acylamino,

hydroxy,

aralkyloxy or

loweralkoxy;

R_(n) is hydrogen or loweralkyl;

R₇, r₈, r₉ and R₁₀ may be the same or different and are:

hydrogen,

alkyl,

alkenyl,

alkynyl,

cycloalkyl or

aralkyl;

R₇ and R₈ together and R₉ and R₁₀ together may form a 5-7 atom ringwhich may further include 0-1 hetero atoms of N, O or S;

x is 0-1;

the sum total of carbon atoms present in R₇, R₈, R₉ and R₁₀ together isless than twelve; and

the non-toxic acid addition salts thereof.

In any discussion of the true structure of an amidinourea, tautomerismmust be considered. It should be clear to anyone skilled in the art thatthe amidinourea sidechain can be legitimately represented in any one ofseveral tautomeric and geometric modifications.

The total number of possible variations in structure is quite high, butit is true to say that these variations can and, to some extent, dooccur when these compounds are in solution.

One form may predominate over another depending upon the degree andlocation of substitution and on the nature of the solvent. The rates ofconversion of one tautomer to another will depend upon the nature of thesolvent, the degree of hydrogen bonding permitted, the temperature andpossibly other factors (such as pH, trace impurities and the like).

To illustrate what is meant by this, a number of likely structures arehere shown for just one of the compounds in this invention. ##STR2##

Of course, other types of structures are possible such as those withhydrogen bonding. ##STR3##

No attempt is made to exhaust the possible structures, for these arelegion. The structures given are representative of the kind ofphenomenon we are trying to describe and are encompassed within thescope of this invention.

It is predictable that in physiological conditions, any or all of thesestructures may exist or even predominate at the sites at which thesemolecules operate.

Tautomerism, of course, by definition only applies to protons and not toother groups. Thus, in the example given, free conversion betweenstructures occurs smoothly by transference of a single proton. At a timewhere other substituents are concerned, tautomerism is to just thatextent ruled out. For example where there are no protons at all becauseof full substitution, only one structure may be reasonably said to existsuch as: ##STR4##

Compounds of this invention which are preferred include those where:

R₂ and R₆ are

halo,

loweralkyl,

haloloweralkyl,

nitro or

loweralkoxy;

R₃ and R₅ are hydrogen;

R₄ is hydrogen,

halo,

loweralkyl,

amino,

acylamino or

hydroxy;

R₇, r₉ and R_(n) are hydrogen or alkyl; R₇ and R₉ may also be aralkyl;

R₈ and R₁₀ are hydrogen, loweralkyl, alkenyl or alkynyl; and

R₇ and R₈ together and R₉ and R₁₀ together are alkylidenyl; and

x is 0-1.

The more preferred compounds of this invention include those where:

R₂ is halo or loweralkyl;

R₃, r₄ and R₅ are hydrogen;

R₆ is

loweralkyl,

nitro,

haloloweralkyl,

loweralkoxy or

halo;

R₇, r₉ and R_(n) are hydrogen or alkyl; R₇ and R₉ may also be aralkyl;

R₈ and R₁₀ are hydrogen or loweralkyl;

R₇ and R₈ together and R₉ and R₁₀ together are alkylidenyl; and

x is 0-1.

The most preferred compounds of this invention are those where:

R₂ is

chloro,

bromo,

fluoro,

methyl or

ethyl;

R₃, r₄ and R₅ are hydrogen;

R₆ is

methyl,

ethyl,

nitro,

methoxy,

ethoxy,

chloro,

bromo or

fluoro;

R_(n) is

hydrogen,

methyl or

ethyl, and

R₈ and R₁₀ are

hydrogen,

methyl or

ethyl;

R₇ and R₉ are

hydrogen,

methyl,

ethyl,

propyl,

i-propyl,

butyl,

i-butyl,

sec-butyl,

t-butyl,

pentyl,

hexyl,

heptyl or benzyl; and

x is 0.

A special embodiment of this invention comprises compounds where:

R₂ is

chloro,

bromo,

fluoro,

methyl or

ethyl;

R₃, r₄ and R₅ are hydrogen,

R₆ is

methyl,

ethyl,

nitro,

methoxy,

ethoxy,

chloro,

bromo or

fluoro;

R_(n) is

hydrogen,

methyl or

ethyl, and

R₇ and R₈ together are trimethylene and tetramethylene;

R₉ and R₁₀ are

hydrogen,

methyl,

ethyl or

together are trimethylene or tetramethylene; and

x is 0.

It is well known in the pharmacological arts that non-toxic acidaddition salts of pharmacologically active amine compounds do not differin activities from their free base. The salts merely provide aconvenient solubility factor.

The amines of this invention may be readily converted to their non-toxicacid addition salts by customary methods in the art. The non-toxic saltsof this invention are those salts the acid component of which ispharmacologically acceptable in the intended dosages; such salts wouldinclude those prepared from inorganic acids, organic acids, higher fattyacids, high molecular weight acids, etc., and include such as:

    ______________________________________                                        hydrochloric acid,  succinic acid,                                            hydrobromic acid,   glycolic acid,                                            sulfuric acid,      lactic acid,                                              nitric acid,        salicylic acid,                                           phosphoric acid,    benzoic acid,                                             methane sulfonic acid,                                                                            nicotinic acid,                                           benzene sulfonic acid,                                                                            phthalic acid,                                            acetic acid,        stearic acid,                                             propionic acid,     oleic acid,                                               malic acid,         abietic acid, etc.                                        ______________________________________                                    

The nomenclature applied to the compounds of this invention is based onthe urea moiety as follows: ##STR5##

The term "loweralkyl" refers to an alkyl hydrocarbon group from 1 to 5carbon atoms which may be straight chained or branched while "alkyl"refers to an alkyl hydrocarbon group which may have as many as tencarbon atoms.

The term "alkenyl" refers to an alkenyl hydrocarbon chain having 3-7carbon atoms.

The term "alkynyl" refers to an alkynyl hydrocarbon chain having 3-7carbon atoms.

The term "cycloalkyl" refers to a cycloalkyl group having 3-7 carbonatoms.

The "loweralkoxy" radical signifies an alkoxy group containing from 1 toabout 5 carbon atoms which may be straight chained or branched.

The preferred "aryl" group is phenyl.

The preferred "aralkyl" groups are benzyl and phenethyl.

The preferred "haloloweralkyl" group is trifluoromethyl.

The compounds of this invention may be prepared by the following generalsynthesis.

Condensation of a substitutedphenyl isocyanate (prepared from an anilineand phosgene in the customary manner) with an N-oxygenated guanidineresults in a 3-substitutedphenyl-1-(N-oxyamidino)urea. The reaction iscarried out in a polar medium using solvents such as dimethylformamide,tetrahydrofuran, etc. ##STR6##

When it is desired to have R_(n) substitution at the N-3 position, thestarting material of course will be an aniline having N-alkylsubstitution. Reaction with phosgene results in the carbamoyl chloridewhich is then reacted with the N-oxygenated guanidine to prepare the3-substitutedphenyl-3-alkyl-1-(N-oxyamidino)urea. ##STR7##

The guanidine starting materials are either known or may be prepared bythe following general reactions.

Reaction of an alkyl halide with N-hydroxyphthalimide in the presence ofbase followed by acid hydrolysis results in the oxyamine. Thiscondensation may be carried out in the presence of an inorganic,alkoxide or tertiary amine base (preferably triethylamine is used) in apolar medium (preferably alcohol or DMF), and at room temperature. Theacid hydrolysis is carried out in strong inorganic acid conditions orhydrazine in ethanol; however acetic acid/conc. HCl is preferred. Thehydrolysis results in the alkoxyamine and phthalic acid and isolationmay be carried out in the normal manner with separation by thehydrochloride salt preferred. When other R₇, R₈, R₉ and R₁₀ groups otherthan alkyl are preferred, then the starting halide would be theappropriate alkenyl halide, alkynyl halide, cycloalkyl halide or aralkylhalide.

Reaction of the oxyamine with a substituted pseudothiouronium salt inaqueous or alcoholic solution gives the N-oxygenated guanidine. This maybe carried out at any convenient temperature between room temperatureand reflux of the reaction mixture. ##STR8## where HX is a mineral acid.

When an N-hydroxyurethan is reacted with two equivalents of an alkylhalide in alcoholic basic medium (preferably alcoholic KOH) then thecorresponding N-alkyl-N-oxyurethan is prepared. This may then behydrolyzed to the amine and reacted as above with a suitablepseudothiouronium salt. ##STR9##

When it is desired to have two alkoxy groups present in the guanidine,then the pseudothiouronium used should be an N-oxy pseudothiouroniumsalt which is reacted with the alkoxyamine ##STR10##

We have found that the compounds of this invention have usefulantiulcerogenic properties. Further they have an effective degree ofgastric anti-secretory activity and effectively reduce the volume andthe acidity of the gastric fluid in humans and mammals. Still further,these compounds produce a considerable spasmolytic action on thegastrointestinal musculature, i.e., they reduce the peristaltic actionof the gastrointestinal musculature which is manifested by a delay ingastric emptying time.

Until now, the known antiulcerogenic compounds which showed gastricanti-secretory and gastrointestinal spasmolytic action have includedsuch agents as atropine, homatropine, propantheline, dicyclomine, etc.These compounds, however, cause accompanying undesirableanti-cholinergic properties such as mydriasis, xerostomia, cyclopegia,etc.

We have found that the N-oxygenated amidinoureas of this invention areparticularly useful as anti-secretory, anti-spasmodic andanti-ulcerogenic agents because they are essentially devoid of theseunwanted effects.

In particular the N-oxygenated amidinoureas as herein described areuseful in the treatment of such ulcerogenic disorders and diseases asduodenal ulcer and peptic ulcer.

The instant compounds may be used alone or in combination with otherknown antacids such as aluminum hydroxide, magnesium hydroxide,magnesium trisilicate, aluminum glycinate, calcium carbonate and thelike.

For all these purposes, N-oxygenated amidinoureas of this invention canbe normally administered orally or parenterally. Orally they may beadministered as tablets, aqueous or oily suspension, dispersible powdersor granules, emulsions, hard or soft capsules, or syrups or elixirs. Theterm parenteral as used herein, includes subcutaneous injection,intravenous, intramuscular or intrasternal injection or infusiontechniques.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apharmaceutically elegant and palatable preparation.

Further, these compounds may be tableted or otherwise formulated so thatfor every 100 parts by weight of the composition, there are presentbetween 5 and 95 parts by weight of the active ingredient. The dosageunit form will generally contain between 1 mg. and about 500 mg. of theactive ingredients of this invention. The preferred unit dose is betweenabout 10 mg. and about 100 mg.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Thus, ingeneral, the dosages are those that are therapeutically effective in thetreatment of ulcerogenic disease conditions or symptoms, such asduodenal and peptic ulcer. In general, the daily dose can be betweenabout 0.1 mg/kg and 150 mg/kg (preferably in the range of 1-100mg/kg/day), bearing in mind, of course, that in selecting theappropriate dosage in any specific case, consideration must be given tothe patient's weight, general health, age and other factors which mayinfluence response to the drug.

Various tests in animals have been carried out to show the ability ofthe compounds of this invention to exhibit reactions that can becorrelated with anti-ulcerogenic activity in humans. These tests involvesuch as the effect of the N-oxygenated amidinoureas on gastric secretionand gastro-intestinal spasm. It has been found that the compounds ofthis invention when tested in the above variety of situations show amarked activity.

One such test is the gastric secretion test. This test is carried out asfollows: Shay rats are fasted for 4-8 hours, and water is given ad lib.The rats are selected at random and separated into groups of 10. Theanimals are treated intraduodenally (I.D.) with the test compound or thevehicle immediately subsequent to the ligation of the stomach at thepyloric sphincter. The animals are sacrificed with chloroform at 4 hourspost-drug administration, the stomach is removed and its contents areassayed for volume, pH and total acids.

A second gastric secretion test is carried out on dogs. This is outlinedin the Handbook of Physiology, Section 6: Alimentary Canal, Volume II:Secretion, American Physiology Society, Washington, D.C., 1967.

It has been found that the compounds of this invention when subjected tothe above gastric secretion tests display a marked ability to decreasegastric volume and gastric acidity. These tests are known to correlatewell with gastric activity in humans and is a standard test used todetermine anti-secretory properties.

To determine the anti-ulcer effectiveness, the following test isemployed: Shay rats are fasted for 4-8 hours, and water is given ad lib.The rats are selected at random and separated into groups of ten. Theanimals are treated intraduodenally (I.D.) with the test compound or thevehicle immediately subsequent to the ligation of the stomach at thepyloric sphincter. The animals are sacrificed with chloroform at 22hours post-drug administration, the stomach is removed and checked forulcers which are then rated along with the survival rate.

A second test employed involves cysteamine induced ulcers following theprocedure as outlined in Digestion 11 198-214 (1974) A. Robert, J. E.Nezamis, C. Lancaster and J. N. Badalamenti.

Uterine motility may be determined by the method described in the Can.J. Physical Pharmacal 49: 988-998, 1971 Ivo Polecek and Edwin E. Daniel.

Pepsin inhibition may be determined following the methods of Chiang. L.et al., Proc. Sec. Expth. Biol. Med., 22: 700, 1966 and Anson, M. L. andMirsky, A. E., J. Gen. Physical 16: 159, 1932.

In view of the results of these tests, the pharmacological data clearlyindicates that the amidinoureas of this invention can be considered tobe effective anti-ulcerogenic agents having active gastricanti-secretory and anti-spasmodic properties which are substantiallyfree of anti-cholinergic side effects and having a low toxicity.

The compounds described in this application are also usefulantidiarrheal agents. For these purposes they can be administeredorally, parenterally or rectally. Administration by the oral route ispreferred. Orally, these compounds may be administered in tablets, hardor soft capsules, aqueous or oily suspensions, dispersible powders orgranules, emulsions, syrups or elixers. The optimum dosage, of course,will depend on the particular compound being used and the type andseverity of the condition being treated. In any specific case theappropriate dosage selected will further depend on factors of thepatient which may influence response to the drug; for example, generalhealth, age, weight, etc. of the subject being treated.

Although the optimum quantities of the compounds of this invention to beused as anti-diarrheal agents will depend on the compound employed andthe particular type of disease condition treated, oral dose levels ofpreferred compounds when administered to a mammal in dosages of 0.01 to500 milligrams per kilogram of body weight per day are particularlyuseful. The preferred range is 0.05 to 200 mg/kg. Comparative dosagesmay be used in parenteral or rectal administration.

Compositions intended for oral use may be prepared according to methodsknown to the art for the manufacture of pharmaceutical compositions.Such compositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents,preserving agents, etc. in order to provide a pharmaceutically elegantand palatable preparation.

Further the active amidinourea may be administered alone or in admixturewith other agents having the same or different pharmacologicalproperties.

The composition may contain such selected excipients such as inertdiluents such as calcium carbonate, lactose, etc.; granulating anddisintegrating agents such as maize starch, alginic acid, etc.;lubricating agents such as magnesium stearate, etc.; binding agents suchas starch gelatin; etc.; suspending agents such as methylcellulose,vegetable oil, etc.; dispersing agents such as lecithin, etc.;thickening agents such as beeswax, hard paraffin, etc.; emulsifyingagents such as naturally-occurring gums, etc.; non-irritating excipientssuch as cocoa butter, polyethylene glycols, etc.; and the like. Further,in formulating these compounds for every 100 parts by weight of thecomposition, there may be present between 5 and 95 parts by weight ofthe active ingredient. The dosage unit form will generally containbetween 0.1 mg. and about 500 mg. of the active ingredients of thisinvention. The preferred unit dose is between 1 mg. and about 50 mg. Thecompositions may be taken 1-8 times daily depending on the dosage unitrequired.

Various tests can be carried out in animal models to show the ability ofthe amidinoureas of this invention to exhibit reactions that can becorrelated with anti-diarrheal activity in humans. The following testsshow the ability of the compounds of this invention to inhibit diarrheain animals and are known to correlate well with anti-diarrheal activityin humans. These are considered to be standard tests used to determineanti-diarrhea properties. This correlation can be shown by theactivities of compounds known to be clinically active. In view of theresults of these tests, the amidinoureas of this invention can beconsidered to be anti-diarrheal agents.

1. Fecal output in rate:

The oral ED₅₀ (that dose which would be exposed to reduce fecal outputby 50%) is determined by a method described by Bass et al., 1972.Briefly, the method involves dosing the rats and collecting the fecaloutput over an 8 hour period (4 PM--12 midnight) with the room darkenedstarting at 4:30 P.M.

Ref:--Bass, P., Kennedy, J. A. and Willy, J. N.: Measurement of fecaloutput in rats. Am. J. Dig. Dis. 10: 925-928, 1972.

2. Castor oil test in mice:

Groups of mice are orally dosed with test compound and half hour laterall mice are given 0.3 ml. of castor oil. Three hours after castor oiladministration, all mice are checked for diarrhea and the dose oftesting compound which protected 50% of mice for diarrhea is the ED₅₀dose.

3. Castor oil test in rats:

The test is conducted according to Nie megeers et al. 1972. The rat isorally dosed with graded doses of test compound. One hour after dosing,each animal is challenged with 1 ml. of castor oil orally. Fecal outputis examined 1, 2, 3, 4, 6, and 8 hours after castor oil. Absence ofdiarrhea is criterion of drug effectiveness.

Ref:--Niemegeers, C. J. E., Lenaerts, F. M. and Janssen, P. A. J.Difenoxine, a potent, orally active and safe anti-diarrheal agent inrats. Arzneim-Forscth (Drug Res.) 22, 516-1518, 1972.

EXAMPLE 1 1-(2,6-Dimethylphenyl)-3-methoxyamidinourea Hydrochloride

To a suspension of 12.0 g. (0.11 mole) of methoxyguanidine hydrochloridein tetrahydrofuran (100 ml.) is added 8.8 g. (0.11 mole) of fiftypercent (w/w) aqueous sodium hydroxide. After one hour of stirring, 5.0g. of anhydrous sodium sulfate is added and the mixture is stirred foran additional hour. A solution of 14.7 g. (0.1 mole) of2,6-dimethylphenylisocyanate in tetrahydrofuran (30 ml.) is addeddropwise after which the mixture is stirred at room temperatureovernight. The tetrahydrofuran is removed under vacuum and the residuepartitioned between water and chloroform. The layers are separated andthe aqueous layer extracted with chloroform (4×100 ml.). The combinedorganic extracts are washed with water (1×50 ml.), dried over anhydrousmagnesium sulfate and filtered. The filtrate is acidified with etherealHCl and the solvents removed in vacuo to give a brown oil which iscrystallized from acetonitrile to give1-(2,6-dimethylphenyl)-3-methoxyamidinourea hydrochloride, m.p. 170°-1°C.

EXAMPLE 2 1-(2,6-Diethylphenyl)-3-(N-methoxy-N' -methylamidino)ureaHydrochloride

To a suspension of 10.0 g. (30.0 mmol) of N-methoxy-N'-methyl guanidinepicrate in tetrahydrofuran (60 ml.) are added 2.4 g. (30.0 mmol) offifty percent (w/w) aqueous sodium hydroxide and the mixture stirred for11/2 hours. Five (5.0) grams of anhydrous sodium sulfate is added andthe mixture stirred for an additional one-half hour. To this mixture isadded a solution of 4.8 g. (30.0 mmol) of 2,6-diethylphenylisocyanate intetrahydrofuran (20 ml.) and the mixture stirred over night. The mixtureis partitioned between chloroform and water and the layers areseparated. The chloroform layer is washed well with dilute aqueoussodium hydroxide until most of the color is removed then dried overanhydrous magnesium sulfate, filtered and concentrated to give an oilwhich is dissolved in methanol and acidified with methanolichydrochloric acid. The methanol is removed under vacuum to give a gummyfoam which is crystallized from methanol/ethyl acetate to give1-(2,6-diethylphenyl)-3-(N-methoxy-N'-methylamidino)urea hydrochloride,m.p. 159.5°-160.5° C.

EXAMPLE 3 A. N-propoxyphthalimide

A mixture of 212 g. of N-hydroxyphthalimide, 132 g. of triethylamine,160 g. of 1-bromopropane and 500 ml. of dimethylformamide is stirredovernight. The reaction mixture is poured into 4.5 liters of water andis stirred at ice temperature for 11/2 hours. The solid is removed byfiltration, washed with water and dried in vacuo to giveN-propoxyphthalimide, m.p. 51°-3° C.

B. Propoxyamine hydrochloride

A solution of 219 g. of N-propoxyphthalimide in a mixture of 600 ml. ofacetic acid and 300 ml. of concentrated hydrochloric acid is brought toa gentle boil and kept there for thirty minutes. The mixture is cooledand filtered to remove phthalic acid. The filtrate is evaporated todryness and the residue partitioned between water and ether. The aqueouslayer is washed with ether (2×250 ml.), filtered and evaporated invacuo. The resultant white solid is dissolved in absolute ethanol andagain evaporated in vacuo to give, after drying, crystallinepropoxyamine hydrochloride, m.p. 146°-9° C.

C. N-propoxyguanidine hydrochloride

To a solution of 113.2 g. of propoxyamine hydrochloride in 200 ml. ofice cold water there is added 81.2 g. of 50% aqueous sodium hydroxidesolution. The mixture is stirred for thirty minutes and 141.0 g. ofS-methyl-2-thiopseudourea sulfate and 200 ml. of water are added. Themixture is stirred at room temperature for two hours and then heated toreflux for one hour. The mixture is treated with 81.2 g. of 50% aqueoussodium hydroxide filtered and evaporated in vacuo. The residue isslurried in 200 ml. of absolute ethanol, the suspension filtered and thefiltrate evaporated to an oil. The crude oil is dissolved in 300 ml. ofchloroform, the mixture is cooled and filtered to give a clear solutionof the guanidine free base. The chloroform solution is made acidic withmethanolic hydrogen chloride and then evaporated in vacuo to givepropoxyguanidine hydrochloride as a clear viscous oil (m.p. of picrate179°-80° C.).

This procedure is used for making those oxyamines not availablecommercially.

EXAMPLE 4 A. Benzyloxyguanidine

To a solution of 30.0 g. (0.12 moles) of S-methylthiouronium sulfate in200 ml. of H₂ O there is added a solution of 24.6 g. (0.20 moles) ofbenzyloxyamine in 250 ml. of 95% ethanol. The mixture is stirred for 72hours at room temperature. The clear solution is heated at reflux fortwo hours under a stream of nitrogen. The solvents are removed in vacuoand the residue is treated with 300 ml. of isopropanol. The solid isremoved by filtration and dissolved in 300 ml. of water. The solution ismade basic with 90 ml. of 10% aqueous sodium hydroxide. The precipitateis collected, washed with water and dried to give benzyloxyguanidine,m.p. 104°-5° C.

B. 1-(2,6-dimethylphenyl)-3-benzyloxyamidinourea hydrochloride

To a solution of 9.20 g. (0.056 moles) of benzyloxyguanidine in 100 ml.of tetrahydrofuran there is added dropwise a solution of 8.30 g. (0.056moles) of 2,6-dimethylphenylisocyanate in 100 ml. of tetrahydrofuran.After stirring for 2 hours the solvent is removed in vacuo and theresidue partitioned between water and chloroform. The chloroform isdried over sodium sulfate, filtered and acidified with saturatedmethanolic hydrogen chloride. The solvents are removed in vacuo and theresultant foam crystallized from 200 ml. of hot ethyl acetate to give1-(2,6-dimethylphenyl)-3-benzyloxyamidinourea hydrochloride, m.p.162°-3° C.

C. 1-(2,6-dimethylphenyl)-3-hydroxyamidinourea hydrochloride

To a solution of 6.0 g. (0.017 moles) of1-(2,6-dimethylphenyl)-3-benzyloxyamidinourea in 160 ml. of absoluteethanol there is added 1.0 g. of 5% Pd/carbon and then 1 ml. ofsaturated ethanolic hydrogen chloride. The mixture is hydrogenated atroom temperature and atmospheric pressure until one equivalent ofhydrogen is taken up (1 hour). The suspension is filtered through a bedof celite and the filtrate evaporated to an off-white solid. The solidis recrystallized from 150 ml. of 7:1 acetonitrile:methanol to give1-(2,6-dimethylphenyl)-3-hydroxyamidinourea hydrochloride, m.p. 191°-2°C.

EXAMPLE 5 A. N-Carbethoxyisooxazolidine

Trimethylene dibromide (40.4 g; 0.4 mole) and an ethanolic solution (224ml.) containing potassium hydroxide (22.4 g.; 0.4 mole) are boiledtogether on a steam bath for six hours. The ethanol is removed bydistillation and the residue triturated with ether (3×100 ml.). Thecombined ether washes are dried over anhydrous magnesium sulfate,filtered and concentrated to give a liquid which is vacuum distilled togive N-carbethoxyisooxazolidine, b.p. 103° C./13 mm.

B. Isooxazolidine Hydrochloride

A mixture of 20.5 g. (0.14 moles) of N-carbethoxyisooxazolidine and 18%aqueous hydrochloric acid (100 ml) are refluxed on a steam bath for twohours. After cooling, the solution is extracted with ether (1×30 ml.)and evaporated to dryness under reduced pressure, the last traces ofwater being removed by evaporation with absolute ethanol. The residue iscrystallized from ethanol/ether to give Isooxazolidine hydrochloride,m.p. 124°-5° C.

C. N-amidino-isooxazolidine sulfate

To 14.5 g. (0.13 mole) of isooxazolidine hydrochloride in water (100ml.) is added 10.4 g. (0.13 mole) of fifty percent (w/w) aqueous sodiumhydroxide and the mixture stirred for fifteen minutes. To this solutionis added 18.1 g. (0.065 moles) of 2-methyl-2-thiopseudourea sulfate andthe entire mixture stirred under a stream of nitrogen overnight. Themixture is refluxed for 11/2 hours, then filtered while still hot. Thewater is removed under vacuum to give a semi-solid residue which istriturated with hot isopropanol (3×100 ml.). The isopropanol is removedunder vacuum to give an oil which is crystallized from isopropanol togive N-amidinoisooxazolidine sulfate.

D. N-[(2,6-Dimethylphenylcarbamoyl)amidino] isooxazolidine Hydrochloride

To 2.9 g. (36.0 mmol) of fifty percent (w/w) sodium hydroxide suspendedin tetrahydrofuran (50 ml.) is added 6.0 g. (18.0 mmol) ofN-amidinoisooxazolidine sulfate and the mixture stirred for one hour.Five (5.0) grams of anhydrous sodium sulfate are added and the mixturestirred for an additional hour. To this mixture are added 5.4 g. (36.0mmol) of 2,6-dimethylphenylisocyanate and the mixture stirred for threehours. Thin layer chromatography (ethyl acetate) showed no startingisocyanate so the tetrahydrofuran is removed under vacuum. The residueis partitioned between water and chloroform. The layers are separatedand the aqueous layer extracted with chloroform (1×100 ml.). Thecombined chloroform extracts are dried over anhydrous magnesium sulfate,filtered and concentrated to give an oil which is dissolved in methanoland acidified (pH=1) with methanolic hydrochloric acid. The methanol isremoved to give an oil which is triturated with diethyl ether to give asolid which is crystallized from tetrahydrofuran/hexane to giveN-[(2,6-dimethylphenylcarbamoyl)amidino] isooxazolidine hydrochloride,m.p. 147°-8° C.

EXAMPLE 6 N,N'-dimethoxyguanidine

To a solution of 50.1 g. of methoxyamine hydrochloride in 200 ml. of icecold water there is added 48.0 g. of 50% aqueous sodium hydroxide. Themixture is stirred for thirty minutes and there is added 149.4 g. ofN-methoxy-S-methylthiouronium iodide and 100 ml. of water. The mixtureis stirred at room temperature for 72 hours and then heated at refluxfor 3 hours. The mixture is cooled and treated with 48.0 g. of 50%aqueous sodium hydroxide. After stirring for thirty minutes, thesolution is evaporated to dryness in vacuo. The residue is trituratedwith 200 ml. of absolute ethanol. The suspension filtered and thefiltrate evaporated in vacuo. The residue dissolved in 150 ml. ofchloroform, the mixture cooled and filtered. The clear filtrateevaporated to a clear viscous oil, N,N'-dimethoxyguanidine, m.p. ofpicrate 160°-2° C.

EXAMPLE 7

Compounds of this invention which are preferred include:

1-(2,6-dimethylphenyl)-3-methoxyamidinourea hydrochloride

1-(2,6-diethylphenyl)-3-methoxyamidinourea succinate

1-(2-bromo-6-methylphenyl)-3-methoxyamidinourea hydrochloride

1-(2-chloro-6-methylphenyl)-3-methoxyamidinourea hydrochloride

1-(2,6-dimethylphenyl)-3-ethoxyamidinourea hydrochloride

1-(2-chloro-6-methyl)-3-ethoxyamidinourea hydrochloride

1-(2,6-dimethylphenyl)-3-n-butoxyamidinourea hydrochloride

1-(2,6-dimethylphenyl)-3-n-propoxyamidinourea hydrochloride

1-(2,6-diethylphenyl)-3-(N-methoxy-N'-methylamidino)urea hydrochloride

1-(2-chloro-6-methylphenyl)-3-(N-methoxy-N'-methylamidino)ureahydrochloride

1-(4-bromo-2,6-diethylphenyl)-3-methoxyamidinourea hydrochloride

1-(4-bromo-2-chloro-6-methylphenyl)-3-methoxyamidinourea hydrochloride

1-(2,6-diethylphenyl)-3-ethoxyamidinourea succinate

1-(4-bromo-2,6-dimethylphenyl)-3-methoxyamidinourea hydrochloride

1-(2,6-diethyl-4-nitrophenyl)-3-methoxyamidinourea hydrochloride

N-[(2,6-dimethylphenylcarbamoyl)amidino]isooxazolidine hydrochloride

1-(2-chloro-6-methylphenyl)-3-n-butoxyamidinourea hydrochloride

1-(1-naphthyl)-3-methoxyamidinourea hydrochloride

1-(2,6-diethylphenyl)-3-n-propoxyamidinourea succinate

1-(2,6-dibromo-4-ethylphenyl)-3-methoxyamidinourea hydrochloride

1-(4-amino-2,6-diethylphenyl)-3-methoxyamidinourea dihydrochloride

1-(2,6-dimethylphenyl)-3-hydroxyamidinourea hydrochloride

1-(2,6-dimethylphenyl)-3-benzyloxyamidinourea hydrochloride

N-[(2,6-dimethylphenylcarbamoyl)amidino]isooxazine hydrochloride

1-(2,6-diethylphenyl)-3-n-butoxyamidinourea succinate

N-[(2,6-diethylphenylcarbamoyl)amidino]isooxazine hydrochloride

1-(2-chloro-6-methylphenyl)-3-n-propoxyamidinourea hydrochloride

We claim:
 1. The method for the treatment of gastrointestinal secretoryand ulcerogenic disease conditions or symptoms in a mammal comprisingadministering thereto between 0.1 mg/kg. and 150 mg/kg. of an effectivedose of a compound of the formula: ##STR11## where: R₂, R₃, R₄, R₅ andR₆ may be the same or different and are:hydrogen, halo, loweralkyl,haloloweralkyl, nitro, amino, acylamino, hydroxy, aralkyloxy orloweralkoxy; R_(n) is hydrogen or loweralkyl; R₇, r₈, r₉ and R₁₀ may bethe same or different and are:hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl or aralkyl; and x is 0-1; the sum total of carbon atomspresent in R₇, R₈, R₉ and R₁₀ together is less than twelve; and thenon-toxic acid addition salts thereof.
 2. The method of claim 1wherein:R₂ and R₆ arehalo, loweralkyl, haloloweralkyl, nitro orloweralkoxy; R₃ and R₅ are hydrogen; R₄ ishydrogen, halo, loweralkyl,amino, acylamino or hydroxy; R₇, r₉ and R_(n) are hydrogen or alkyl; R₇and R₉ may also be aralkyl; R₈ and R₁₀ arehydrogen, loweralkyl, alkenylor alkynyl; x is 0-1.
 3. The method of claim 2 wherein:R₂ is halo orloweralkyl; R₃, r₄ and R₅ are hydrogen; R₆ isloweralkyl, nitro,haloloweralkyl, loweralkoxy or halo; R₇, r₉ and R_(n) are hydrogen oralkyl; R₇ and R₉ may also be aralkyl; and R₈ and R₁₀ are hydrogen orloweralkyl; and x is 0-1.
 4. The method of claim 3 wherein:R₂ ischloro,bromo, fluoro, methyl or ethyl; R₃, r₄ and R₅ are hydrogen; R₆ ismethyl,ethyl, nitro, methoxy, ethoxy, chloro, bromo or fluoro; R_(n)ishydrogen, methyl or ethyl, R₈ and R₁₀ arehydrogen, methyl or ethyl; R₇and R₉ arehydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,sec-butyl, t-butyl, pentyl, hexyl, heptyl or benzyl; and x is
 0. 5. Themethod of claim 1 wherein:R₂ ischloro, bromo, fluoro, methyl or ethyl;R₃, r₄ and R₅ are hydrogen, R₆ ismethyl, ethyl, nitro, methoxy, ethoxy,chloro, bromo or fluoro; R_(n) ishydrogen, methyl or ethyl, R₇ and R₈together are trimethylene or tetramethylene; R₉ and R₁₀ arehydrogen,methyl, ethyl or together are trimethylene or tetramethylene; and x is0.
 6. The method of claim 4 wherein R₇ is butyl.
 7. The method of claim4 wherein R₇ is i-butyl.
 8. The method of claim 4 wherein theadministered compound is 1-(2,6-dimethylphenyl)-3-n-butoxyamidinourea.9. The method of claim 4 wherein said administered compound is anon-toxic acid addition salt of1-(2,6-dimethylphenyl)-3-n-butoxyamidinourea.